This invention is in the field of synthetic organic chemistry. This invention pertains to a method to produce xcex1-methylenelactones and xcex1-substituted hydrocarbylidene lactones. More specifically, this invention pertains to a simple, efficient and economic method to produce xcex1-methylene-xcex3-butyrolactone from xcex3-butyrolactone.
xcex1-Methylenelactones have been the subject of intensive synthetic studies. Specifically, the xcex1-methylene-xcex3-butyrolactone group is an important structural feature of many sesquiterpenes of biological importance. In addition, xcex1-methylene-xcex3-butyrolactones are regarded as potential key monomers in both homopolymers and copolymers. One main use for xcex1-methylene-xcex3-butyrolactone is as an intermediate for the production of 3-methyltetrahydrofuran. Currently the cost of xcex1-methylene-xcex3-butyrolactone is too high to warrant commercial production of the resulting polymers. Some of the current synthetic routes suffer from low yields, byproduct formation and expensive starting materials.
An early synthesis of xcex1-methylene-xcex3-butyrolactone involves two steps (Martin et al., J. Chem. Soc. D 1:27 (1970)). The first is carboxylation of xcex3-butyrolactone with methyl methoxymagnesium carbonate (Stiles"" reagent) to produce the acid. Next, the acid is briefly treated with a mixture of aqueous formaldehyde and diethylamine, followed by a separate treatment of the crude product with sodium acetate in acetic acid. The first step requires 6-7 hours and affords almost quantitative yields, whereas the second step can be accomplished in less than 30 minutes but with yields of only 50%.
Murray et al. (Synthesis 1:35-38 (1985); see also U.S. Pat. No. 5,166,357) disclose a route to xcex1-methylene-xcex3-butyrolactone that also involves a two-step sequence consisting of the reaction of xcex3-butyrolactone with ethyl formate in the presence of base, followed by refluxing the resulting xcex1-formyl-xcex3-butyrolactone sodium salt under nitrogen with paraformaldehyde in tetrahydrofuran. Distillation affords the desired xcex1-methylene-xcex3-butyrolactone as a colorless oil. This reaction sequence can best be explained by formyl transfer from carbon to oxygen followed by elimination of carboxylate anion.
Essentially all approaches to xcex1-methylene-xcex3-butyrolactone are liquid-phase processes. One exception is the vapor-phase process described in JP 10120672, which involves subjecting xcex3-butyrolactone or an alkyl-substituted xcex3-butyrolactone, in which one or more hydrogen atoms at the xcex2- or xcex3-position of the xcex3-butyrolactone are substituted with C1-C18 alkyl groups, to a gaseous phase catalytic reaction using a raw material gas containing formaldehyde or its derivative in the presence of a catalyst. Molecular oxygen is preferably added to the raw material gas and the catalyst is preferably silica alumina catalyst. Specifically, a gaseous mixture of xcex3-butyrolactone, formaldehyde, water, nitrogen and oxygen are passed through a reactor packed with Wakogel C-200, pretreated with an aqueous potassium hydroxide solution and heated at 330xc2x0 C., to afford xcex1-methylene-xcex3-butyrolactone at a conversion of 35.5% and a selectivity of 46.9%.
The synthetic approaches to date typically involve two-step processes that use highly flammable solvents such as tetrahydrofuran (THF) or diethyl ether. Impurities are often present at high concentrations and the final distillation leaves significant amounts of residual polymer. In McMurry""s synthesis of xcex1-methylene-xcex3-butyrolactone (J. Org. Chem. 42:1180-5 (1977)), a solution of xcex3-butyrolactone and diethyl oxalate is added to a cooled solution of sodium ethoxide in ethanol. The xcex1-oxalyl sodium salt is formed in solution. The solvent is removed in vacuo and the residual pasty material is taken up in water and diethyl ether and then acidified to give the xcex1-ethyl oxalyl xcex3-butyrolactone (vide infra). This compound is then dissolved in THF and added to a cooled suspension of lithium hydride in THF. Formaldehyde gas is bubbled in to produce xcex1-methylene-xcex3-butyrolactone. The final overall yield is reported to be 83%. While this process affords xcex1-methylene-xcex3-butyrolactone in fairly high yield and purity, it is not readily adapted to large scale reactions required for polymer production.
Although the above methods for the production of xcex1-methylene-xcex3-butyrolactone and xcex1-substituted hydrocarbylidene lactones are useful, they are time consuming and do not obtain high product purity. In addition, the known methods are not readily adaptable to large scale reactions. Another problem is to find a more effective and economical method of production than are currently available. The present method offers a user-friendly process resulting in high yields and good selectivity. Furthermore, the process eliminates high levels of the residual xcex3-butyrolactone starting material which has been shown to limit the scope of polymerization methods used in the production of xcex1-methylene-xcex3-butyrolactone. The critical advance is the isolation of the intermediate compound which is crucial in obtaining high purity of the xcex1-methylene-xcex3-butyrolactone and xcex1-substituted hydrocarbylidene lactone product as a result of the method presented herein.
The instant invention relates to a process for preparing xcex1-methylenelactones of Formula III comprising the steps:
(a) contacting lactones of Formula I with an oxalate in the presence of a base and a solvent to form an intermediate mixture comprising the compound of Formula II and isolating the compound of Formula II from the intermediate mixture
(b) treating the isolated compound of Formula II with formaldehyde to form a product mixture; and
(c) optionally isolating the xcex1-methylenelactones of Formula III from the product mixture. 
xe2x80x83wherein,
n=1-11;
R is hydrocarbyl or substituted hydrocarbyl;
X is a cation; and
R1, R2, R3 and R4, taken independently are hydrogen, hydrocarbyl or substituted hydrocarbyl, C1-C18 unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl containing at least one heteroatom, unsubstituted or substituted aromatic ring, and unsubstituted or substituted aromatic ring containing at least one heteroatom.
The invention further provides a process for the preparation of compounds of Formula III wherein any two of R1, R2, R3 and R4 are members of a ring structure selected from the group consisting of, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl containing at least one heteroatom in the ring, unsubstituted or substituted aromatic ring, and unsubstituted or substituted aromatic ring containing at least one heteroatom in the ring.
Another embodiment of the invention is a process for preparing xcex1-substituted hydrocarbylidene lactones of Formula IV comprising the steps:
(a) contacting lactones of Formula I with an oxalate in the presence of a base and a solvent to form an intermediate mixture comprising the compound of Formula II and isolating the compound of Formula II from the intermediate mixture;
(b) treating the isolated compound of Formula II with a formaldehyde derivative to form a product mixture; and
(c) optionally isolating the xcex1-substituted hydrocarbylidene lactones of Formula IV from the product mixture. 
xe2x80x83wherein,
n=1-11;
R is hydrocarbyl or substituted hydrocarbyl;
X is a cation; and
R is hydrocarbyl or substituted hydrocarbyl; and
R1, R2, R3 and R4 taken independently are hydrogen, hydrocarbyl or substituted hydrocarbyl, C1-C18 unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl containing at least one heteroatom, unsubstituted or substituted aromatic ring, and unsubstituted or substituted aromatic ring containing at least one heteroatom.
The invention further provides a process for the preparation of compounds of Formula IV wherein any two of R1, R2, R3 and R4 are members of a ring structure selected from the group consisting of, hydrocarbyl or substituted hydrocarbyl, C1-C18 unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl containing at least one heteroatom in the ring, unsubstituted or substituted aromatic ring, and unsubstituted or substituted aromatic ring containing at least one heteroatom in the ring.
In the first step of the processes the base is metal alkoxide, metal carbonate, oxide, hydroxide or phosphate or mixtures thereof and may be supplied in homogeneous or heterogeneous form. The first step of the process is conducted at a temperature range of at least about 25xc2x0 C. and a pressure less than or equal to 2000 psi, preferable about 75xc2x0 C. and atmospheric pressure. The reaction may optionally run at higher temperatures, at about 100xc2x0 C. to about 120xc2x0 C. under higher pressures of about 700 psi. The reaction may optionally employ an organic solvent and use a phase transfer catalyst. The second step of the process is conducted at a temperature range of at least about 0xc2x0 C. and a pressure less than or equal to 2000 psi, preferably 10xc2x0 C. and atmospheric pressure. The first step of the process can employ any number of solvents or combinations thereof, these include but are not limited to methanol, ethanol and isopropanol. The second step of the process can employ any number of solvents or combinations thereof, these include but are not limited to water, toluene, xylenes, hexanes, ethyl acetate, chlorobenzene, 1,2-dichlorobenzene, acetonitrile, methylene chloride, acetone, methyl ethyl ketone, dimethylacetamide, chloroform, chlorobutane, benzene and 1-chlorobutane.
The instant invention relates to a process for preparing xcex1-methylenelactones of Formula III comprising heating lactones of Formula I with an oxalate in the presence of a base and solvent, such as sodium methoxide in methanol, to form the xcex1-oxalyl enolate salt of Formula II (Scheme I). If the R group of the base and the R group of the oxalate are different, a mixture of ester R groups in Formula II is obtained. It is recognized that the Formula II may exist as a mixture of E and Z isomers (vide infra) as described in xe2x80x9cFormation of Enolatesxe2x80x9d, Comprehensive Organic Synthesis, 1991, Volume 2, p. 99. The Z enolate (as drawn) is the preferred isomer. This salt is easily prepared on 150 gallon scale and is stable for several months at room temperature. The reaction will work in the absence of a solvent, however the workup would no longer facilitate high space-time yields nor be adaptable to a larger scale process, and would require trituration of the solid reaction mass with a solvent such as petroleum ether. The second step comprises treating the xcex1-oxalyl enolate salt with a formaldehyde source, most preferably aqueous 37% formaldehyde, to give the corresponding xcex1-methylenelactone of Formula II. The xe2x80x9ccrudexe2x80x9d product is greater than 95% pure by gas chromatography (GC) and the final product can be obtained in up to 99.8% purity by GC. The final distillation leaves less than 10% polymer residue in the distillation pot. Compared to previous methods, this process produces xcex1-methylene-xcex3-butyrolactone and its derivatives of Formula III in higher yield and higher purity from ingredients that are readily available in bulk quantities (xcex3-butyrolactone, sodium methoxide, methanol, ethanol, methylene chloride, aqueous formaldehyde and potassium carbonate). 
Wherein,
n=1-11;
R is hydrocarbyl or substituted hydrocarbyl;
X is a cation; and
R1, R2, R3 and R4, taken independently are hydrogen, hydrocarbyl or substituted hydrocarbyl, C1-C18 unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl containing at least one heteroatom, unsubstituted or substituted aromatic ring, and unsubstituted or substituted aromatic ring containing at least one heteroatom.
The invention further provides a process for the preparation of compounds of Formula III wherein any two of R1, R2, R3 and R4 are members of a ring structure selected from the group consisting of, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl containing at least one heteroatom in the ring, unsubstituted or substituted aromatic ring, and unsubstituted or substituted aromatic ring containing at least one heteroatom in the ring.
In another embodiment of the invention, the invention provides a process for preparing xcex1-substituted hydrocarbylidene lactones of Formula IV comprising heating lactones of Formula I with an oxalate in the presence of a base and solvent, such as sodium methoxide in methanol, to form the xcex1-oxalyl enolate salt of Formula II (Scheme 2). The second step comprises treating the xcex1-oxalyl enolate salt with a formaldehyde derivative to give the corresponding xcex1-substituted hydrocarbylidene lactone of Formula IV, 
wherein,
n=1-11;
R is hydrocarbyl or substituted hydrocarbyl;
X is a cation; and
R is hydrocarbyl or substituted hydrocarbyl; and
R1, R2, R3 and R4 taken independently are hydrogen, hydrocarbyl or substituted hydrocarbyl, C1-C18 unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl containing at least one heteroatom, unsubstituted or substituted aromatic ring, and unsubstituted or substituted aromatic ring containing at least one heteroatom.
The invention further provides a process for the preparation of compounds of Formula IV wherein any two of R1, R2, R3 and R4 are members of a ring structure selected from the group consisting of, hydrocarbyl or substituted hydrocarbyl, C1-C18 unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkyl containing at least one heteroatom in the ring, unsubstituted or substituted aromatic ring, and unsubstituted or substituted aromatic ring containing at least one heteroatom in the ring.
When a group contains a substituent which can be hydrogen, for example R1, R2, R3 and R4, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
In the first step of the processes the base is metal alkoxide, metal carbonate, oxide, hydroxide or phosphate or mixtures thereof and may be supplied in a homogeneous or heterogeneous form. The first step of the process is conducted at a temperature range of at least about 25xc2x0 C. and a pressure less than or equal to 2000 psi, preferable about 75xc2x0 C. and atmospheric pressure. The reaction may optionally run at higher temperatures, at about 100xc2x0 C. to about 120xc2x0 C. under higher pressures of about 700 psi. The reaction may optionally employ an organic solvent and use a phase transfer catalyst. The second step of the process is conducted at a temperature range of at least about 0xc2x0 C. and a pressure less than or equal to 2000 psi, preferably 10xc2x0 C. and atmospheric pressure. The first step of the process can employ any number of solvents or combinations thereof, these include but are not limited to methanol, ethanol and isopropanol. The second step of the process can employ any number of solvents or combinations thereof, these include but are not limited to water, toluene, xylenes, hexanes, acetonitrile, methylene chloride, acetone, methyl ethyl ketone, dimethylacetamide, chloroform, chlorobutane, benzene and 1-chlorobutane. The instant invention may optionally use phase transfer catalysts.
In the context of this disclosure, a number of terms and abbreviations shall be utilized. The following definitions are provided.
An xe2x80x9calkylxe2x80x9d is a straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl and hexyl isomers. Also included are all isomers up to and including octadecyl.
xe2x80x9cxcex1-Methylene-xcex3-butyrolactonexe2x80x9d is abbreviated MBL.
xe2x80x9cxcex3-Butyrolactonexe2x80x9d is abbreviated GBL.
xe2x80x9cTetrahydrofuranxe2x80x9d is abbreviated THF.
xe2x80x9cGas chromatographyxe2x80x9d is abbreviated GC.
xe2x80x9cNuclear magnetic resonancexe2x80x9d is abbreviated NMR.
xe2x80x9cMolecular weightxe2x80x9d is abbreviated MW.
xe2x80x9cSodium; ethoxycarbonyl-(2-oxo-dihydro-furan-3-ylidene)-methanolatexe2x80x9d is also known as ethyl oxalyl xcex3-butyrolactone sodium salt.
xe2x80x9cSodium; ethoxycarbonyl-(5-methyl-2-oxo-dihydro-furan-3-ylidene)-methanolatexe2x80x9d is also known as ethyl oxalyl xcex3-methyl-xcex3-butyrolactone sodium salt.
xe2x80x9cSodium; ethoxycarbonyl-(5-penthyl-2-oxo-dihydro-furan-3-ylidene)-methanolatexe2x80x9d is also known as ethyl oxalyl xcex3-pentyl-xcex3-butyrolactone sodium salt.
A xe2x80x9cformaldehyde derivativexe2x80x9d is a compound having the general formula RCHO.
An xe2x80x9coxalatexe2x80x9d is a compound having the general formula ROC(xe2x95x90O)C(xe2x95x90O)OR, wherein R is hydrogen, hydrocarbyl or substituted hydrocarbyl.
A xe2x80x9ccationxe2x80x9d is a molecular entity carrying at least one unit of positive charge formally derived from a parent hydride, a parent compound, or a hydro derivative of either, by the gain of one or more hydrons, by the loss of one or more hydride ions, or a combination of these operations.
A xe2x80x9chydrocarbyl groupxe2x80x9d is a univalent group containing only carbon and hydrogen. If not otherwise stated, it is preferred that hydrocarbyl groups herein contain 1 to about 30 carbon atoms.
A xe2x80x9csubstituted hydrocarbylxe2x80x9d is a hydrocarbyl group which contains one or more substituent groups which are inert under the process conditions to which the compound containing these groups is subjected. The substituent groups also do not substantially interfere with the process. If not otherwise stated, it is preferred that substituted hydrocarbyl groups herein contain from 1 to about 30 carbon atoms. Included in the meaning of xe2x80x9csubstitutedxe2x80x9d are heteroaromatic rings.
A xe2x80x9chomogeneous basexe2x80x9d is a base which is in soluble form and exists in the same phase (solid, liquid or gas) as the reactants.
A xe2x80x9cheterogeneous basexe2x80x9d is a base which operates on reactions taking place on surfaces where the reacting species are held on the surface of the base by adsorption. Typically heterogeneous bases are not in solution and do not exist in the same phase (solid, liquid or gas) as the reactants.
The terms xe2x80x9cE and Zxe2x80x9d are generally accepted stereodescriptors of stereoisomeric alkenes R1R2Cxe2x95x90CR3R4 (R1 is not equal to R2, R3 is not equal to R4; neither R1 nor R2 need be different from R3 or R4). The group of highest CIP (Cahn-Ingold-Prelog) priority attached to one of the terminal doubly bonded atoms of the alkene (i.e. R1 or R2) is compared with the group of highest precedence attached to the other (i.e. R3 or R4). The stereoisomer is designated as Z (zusammen=together) if the groups lie on the same side of a reference plane passing through the double bond and perpendicular to the plane containing the bonds linking the groups to the double-bonded atoms; the other stereoisomer is designated as E (entgegen=opposite). For the purposes of the instant invention, Formula II can be either the E or Z isomer.
One step of the method is the addition of formaldehyde. Formaldehyde may be supplied in a variety of forms including as a solution (in water, methanol or ethanol) or in the form of a formaldehyde polymer. Polymers of formaldehyde are more generally denominated polyacetals and include or are characterized by a linear polymer chain containing recurring xe2x80x94(CH2O)xe2x80x94 units or groups. The preferred polymer of formaldehyde in the composition of the invention is polyoxymethylene which has not been stabilized against thermal degradation as, for example, by end-capping the ends of the linear polymer chain with stabilizing end-groups. Thus, a preferred polymer of formaldehyde is paraformaldehyde, which is a lower molecular weight linear polymer available commercially as a fine powder. Another suitable polymer of formaldehyde is, for example, trioxane. Other polymers of formaldehyde which can be utilized herein are described generally in U.S. Pat. No. 2,768,994, hereby incorporated by reference. Another variety of polymers are sold under the registered trademark Delrin(copyright) acetal resins by E. I. du Pont de Nemours and Company, Inc. Delrin(copyright) acetal resin polymers are usually stabilized against thermal degradation but may still be utilized in the instant invention.
The method is also successful where a formaldehyde derivative is used in place formaldehyde. One group of suitable formaldehyde derivatives are the substituted aldehydes. When formaldehyde is employed in the reaction the group added to the compound of Formula II, (Scheme 1) will be a methylene group. However, if an alkyl-substituted aldehyde is used, e.g., RCHO (Scheme 2), the new group will be an alkyl-substituted hydrocarbylidene group, that is, RCHxe2x95x90. Examples of suitable substituted aldehydes are acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, n-pentanal, 2-methylbutanal, 3-methylbutanal, n-hexanal, 2-methylpentanal, 3,3-dimethylbutanal, 2-ethylhexanal, 2-methyidecanal, and also dialdehydes such as glyoxal, methylglyoxal, malonic dialdehyde, succinic dialdehyde and glutaric dialdehyde, and other aldehydes such as 3-hydroxy-2,2-dimethylpropanol (hydro pivalaidehyde), methoxypivalaldehyde, butoxypivalaldehyde, 4-acetoxybutyaldehyde and 5-formylvaleraldehyde.
The bases of the invention are selected from the metal alkoxides, metal oxides, hydroxides, carbonates and phosphates. The metal alkoxides, oxides, hydroxides, carbonates and phosphates employed herein may be supplied as solutions, powders, granules, or other particulate forms, or may be supported on an essentially inert support as is common in the art of catalysis. Representative bases include, but are not limited to, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium n-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, barium carbonate, sodium hydrogen carbonate, magnesium oxide, barium oxide, barium hydroxide, lanthanum oxide, potassium hydroxide, cadmium oxide, rubidium oxide, lithium hydroxide, strontium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, potassium phosphate and mixtures thereof.
The preferred base in the first step is sodium methoxide (Formula I to Formula II). This ingredient is most often supplied as a 25 wt % solution in methanol. Alternatively, sodium ethoxide, sodium isopropoxide, or sodium hydroxide may be used. At atmospheric pressures the temperature of the reaction can range from about 25xc2x0 C. to about 160xc2x0 C., with a preferred range of about 70xc2x0 C. to about 80xc2x0 C. The process of the present invention may be run at higher temperatures by applying pressures greater than atmospheric.
The bases of the invention may be supported or unsupported. Where a support is desired suitable supports include, but are not limited to, silica, titania, zirconia, alumina, carbon, various zeolites and mixtures thereof.
A base may optionally be used in the second step (Formula II to Formula III and Formula II to Formula IV). The base in the second step is used to neutralize the excess formaldehyde or formaldehyde derivative. This neutralization has been shown to limit byproduct formation (i.e., xcex1-ethyl oxalyl-xcex3-butyrolactone (Formula V), the spiro compound (Formula VI) and polymerization productsxe2x80x94see Example 20). Examples of bases for the second step are ammonia, triethylamine, pyridine, piperidine, pyrrolidinine, pyrrole, dimethylaniline, dimethylaminopyridine, 1,4-diaza[2,2,2]bicycloctane (Dabco), potassium carbonate potassium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, potassium phosphate, sodium phosphate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, sodium borate and potassium borate. The preferred base in the second step is potassium carbonate. 
The present method may optionally employ an organic solvent in the first or second step. Suitable organic solvents include but are not limited to toluene, methylene chloride, acetone, acetonitrile, ethyl acetate, ethanol, isopropanol, methanol, 2,2-diethoxypropane, n-butanol and polyethylene glycols. The preferred solvent for use in the first step is ethanol (Formula I to Formula II). The preferred solvent for use in the second step is methylene chloride (Formula II to Formula III).
Where a solvent is employed the instant invention may optionally also use a phase transfer catalyst. Although a wide variety of phase transfer catalysts are known and used in the chemical industry, certain phase transfer catalysts work more effectively than others for a particular chemical reaction and for individual reactants. An example is tetrabutylammonium bromide. Other phase transfer catalysts useful herein include, but are not limited to, quaternary ammonium salts, quaternary phosphonium salts, crown ethers, and polyethers. For polyethers, the phase transfer catalyst is a member selected from the group consisting of polyethylene glycols (PEG""s) of various molecular weights (MW). PEG""s with an average molecular weight from 200 to  greater than 20,000 are available commercially. The number of repeat units, n, in the PEG is an important factor in its effectiveness as a phase transfer catalyst. Values of n greater than or equal to 8 are generally preferred as phase transfer catalysts. The phase transfer catalyst is used in an amount of 0 to 0.25 parts, preferably 0.05 to 0.10 parts, per part by weight of the reactive substrate. Phase transfer catalysts are common and well known in the art, see for example, Cook et al., Chim. Oggi 16(1/2):44-48 (1998); xe2x80x9cPhase Transfer Catalysis: Fundamentals, Applications, and Industrial Perspectivesxe2x80x9d by C. M. Starks, C. L. Liotta, and M. Halpern., Chapman and Hall, Inc., 1994.
The desired products, including xcex1-methylene-xcex3-butyrolactone, are isolated using techniques common to the art. For example, when allowed to cool the xcex1-methylene-xcex3-butyrolactone reaction mixture forms a pale yellow slurry. This slurry is filtered to remove oxalyl by-products. One can optimize the precipitation of the oxalyl by-products with the solvent composition. In ethyl acetate/toluene (1/0 to 1/1 v/v), acetonitrile/toluene (1/1 v/v), acetone/toluene (1/1 v/v), THF/toluene (1/1 v/v), they precipitate from the reaction to make xcex1-methylene-xcex3-butyrolactone filterable, in toluene or dimethylacetamide it is not. The solvent is then removed in vacuo to give xcex1-methylene-xcex3-butyrolactone that is greater than 95% pure by GC. The (xcex1-methylene-xcex3-butyrolactone may be taken to a higher purity by distillation. This distillation can be done in a batch or a continuous mode to give the final product in up to 99.8% purity as a colorless liquid. Vacuum distillation is the preferred method of distillation, since it decreases the amount of polymerization byproducts.
Alternatively xcex1-methylene-xcex3-butyrolactone can be isolated by steam distillation. Typically, steam is allowed to flow through a distillation apparatus containing xcex1-methylene-xcex3-butyrolactone. The water distillate (containing xcex1-methylene-xcex3-butyrolactone) is then extracted with an organic solvent such as ethyl acetate. The solvent is then removed in vacuo to recover xcex1-methylene-xcex3-butyrolactone.
In another isolation method, xcex1-methylene-xcex3-butyrolactone can also be purified by melt crystallization. In this process, xcex1-methylene-xcex3-butyrolactone is cooled below its melting point (below about xe2x88x9235xc2x0 C.) to form a solid. Liquid impurities are allowed to flow away from the pure, solid xcex1-methylene-xcex3-butyrolactone. The temperature is then raised to melt the xcex1-methylene-xcex3-butyrolactone and recover it in a more pure form. The melt crystallization process can be repeated to obtain high purity xcex1-methylene-xcex3-butyrolactone.
A third isolation method uses a polymerization-depolymerization protocol. A free radical initiator can be added, such an azobisisobutyronitrile or benzoyl peroxide, to the mixture from the second step followed by applying sufficient heat to start a polymerization. A solvent can optionally be added to carry out solution polymerization or use other well known polymerization methods such as bulk and emulsion polymerization. The methylene lactone polymer can then be separated from the by products of this step by well known methods such as precipitation, devolatilization, coagulation or filtration. Once the polymer is obtained in pure form, one can heat it to at least 200xc2x0 C. to start a depolymerization in which the methylene lactone polymer unzips to form methylene lactone which can be isolated by condensation and possibly further purified by any of the mentioned methods in this patent.
The instant invention may optionally employ polymerization inhibitors. Examples include phenolic compounds such as monomethylether hydroquinone, hydroquinone, t-butyl catechol (TBC), 2,4-dimethyl-6-tert-butylphenol (Topanol A), 2,6-di-tert-butyl-4-hydroxytoluene (BHT), pentaerythritol, tetrakis(3,5-di-tert-butyl-4-hydroxyhydrocinnamate). Additionally, nitroxides such as 4-hydrox-tetramethylpiperidinoxyl (4-hydroxy-TEMPO), bis(1-oxyl-2,2,6,6-tetramethylpiperidine-4-yl)sebacate can be used. Substituted p-phenylenediamines such as phenothiazine, N,Nxe2x80x2-bis(1,4-dimethylpentyl)-p-phenylened iamine, N-(1,4-dimethylpentyl)-Nxe2x80x2-phenyl-p-phenylenediamine (Naugard(copyright) I-3 (from Uniroyl Co., Middlebury, Conn.)), N-phenyl-Nxe2x80x2-isopropyl-p-phenylenediamine, 2-sec-butyl-4,6-dinitrophenol (DNBP), N-phenyl-Nxe2x80x2-(1,3-dimethylbutyl)-p-phenylenediamine can also be readily used. Metal complexes such as CuCl2 and FeCl3 can be used too. Furthermore, any mixtures of the above would work in the instant invention. See also Odian, G., In Principles of Polymerization, 2nd Ed; Wiley Interscience, New York, 1981, p 242 and compounds listed therein.
Preferred inhibitors are compounds with a boiling point 40xc2x0 C. higher than that of (xcex1-methylenelactone compounds and which do not form an azeotrope with the xcex1-methylenelactone compounds. Specially preferred are N-(1,4-dimethylpentyl)-Nxe2x80x2-phenyl-p-phenylenediamine (Naugard(copyright) I-3 (from Uniroyal Co., Middlebury, Conn.)), 4-hydroxy-tetramethylpiperidinoxyl (4-hydroxy-TEMPO) and bis(1-oxyl-2,2,6,6-tetramethylpiperidine-4-yl)sebacate in a concentration range of 10 ppm-5 wt %. The preferred concentration is between 0.5-1 wt %.
The present method lends itself to either batch or continuous processes. In the case of (xcex1-methylene-xcex3-butyrolactone preparation, a continuous process employs a pipeline reactor for the xcex3-butyrolactone to xcex1-methylene-xcex3-butyrolactone conversion. Liquid xcex3-butyrolactone is fed into a pipe and mixed with diethyl oxalate in the presence of a base. xcex3-Butyrolactone and diethyl oxalate react to give Formula II as a slurry. This slurry is pumped in to another pipe where formaldehyde is added in a continuous stream. By product solids are filtered and solvent removed to give xcex1-methylene-xcex3-butyrolactone as a pale yellow liquid. A continuous distillation is then performed to obtain purified xcex1-methylene-xcex3-butyrolactone.
It is recognized that some reagents and reaction conditions described for preparing compounds of Formula III and Formula IV may not be compatible with certain functionalities present in the lactone starting material (Formula I). In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps to complete the synthesis of compounds of Formula III and Formula IV. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula III and Formula IV.
Where it is desired to reduce xcex1-methylene-xcex3-butyrolactone to 3-methyltetrahydrofuran, a variety of hydrogenation processes may be coupled with the xcex1-methylene-xcex3-butyrolactone preparative process, with or without isolation of the intermediate xcex1-methylene-xcex3-butyrolactone. Typical hydrogenation would involve the reduction of xcex1-methylene-xcex3-butyrolactone over a hydrogenation catalyst at elevated temperature. Hydrogenation catalysts are common and well known in the art. Those suitable for the present conversion include, but are not limited to, metals such as cobalt, nickel, molybdenum, chromium and palladium.